Overcoming cisplatin resistance

Cisplatin was known to damage DNA and to unleash reactive oxygen species, but the interaction between cisplatin and Mek1/cRaf had not been observed Read more

Fragile X: preclinical portfolio for PI3k drug strategy

An alternative drug strategy for fragile X is gathering strength. Lots of data on behavior and biochemistry from mouse Read more

Stem cells driven into selective suicide

The term “stem cell” is increasingly stretchy. This is one way to get rid of a particular Read more

Cancer

Overcoming cisplatin resistance

Despite being studied for decades, the chemotherapy drug cisplatin is revealing new aspects of how it works. Researchers at Winship Cancer Institute of Emory University have identified an enzyme responsible for making tumors and cancer cell lines resistant to cisplatin, along with an experimental drug that targets that enzyme.

The results were published on July 19 in Cancer Cell.

Winship researcher Sumin Kang, PhD

Cisplatin is a DNA-damaging agent used in standard treatment for lung, head and neck, ovarian, and testicular cancers. It has a simple structure, grabbing DNA with its metallic (platinum) arms to form crosslinks. It used to be known as “cis-flatten” because of its nausea-inducing side effects. The experimental drug, lestaurtinib, has already been tested in clinical studies in combination with other chemotherapy drugs, which means it could easily go into trials against tumors displaying cisplatin resistance.

Sumin Kang, PhD, and colleagues at Winship decided to look for enzymes whose activity was necessary for cancer cells to withstand cisplatin treatment. They chose kinases, enzymes that often control some aspect of cell growth and are have plenty of existing drugs targeting them. The researchers found that in combination with a sub-lethal amount of cisplatin, “knocking down” the activity of the kinase MAST1 kills a cell. But how does that combination work?

Read more

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Nox-ious link to cancer Warburg effect

At Emory, Kathy Griendling’s group is well known for studying NADPH oxidases (also known as Nox), enzymes which generate reactive oxygen species. In 2009, they published a paper on a regulator of Nox enzymes called Poldip2. Griendling’s former postdoc, now assistant professor, Alejandra San Martin has taken up Poldip2.

Griendling first came to Nox enzymes from a cardiology/vascular biology perspective, but they have links to cancer. Nox enzymes are multifarious and it appears that Poldip2 is too. As its full name suggests, Poldip2 (polymerase delta interacting protein 2) was first identified as interacting with DNA replication enzymes.  Poldip2 also appears in mitochondria, indirectly regulating the process of lipoylation — attachment of a fatty acid to proteins anchoring them in membranes. That’s where a recent PNAS paper from San Martin, Griendling and colleagues comes in. It identifies Poldip2 as playing a role in hypoxia and cancer cell metabolic adaptation.

Part of the PNAS paper focuses on Poldip2 in triple-negative breast cancer, more difficult to treat. In TNBC cells, Poldip2’s absence appears to be part of the warped cancer cell metabolism known as the Warburg effect. Lab Land has explored the Warburg effect with Winship’s Jing Chen.

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Exotic immune systems are big business

What timing! Just when our feature on Max Cooper and lamprey immunology was scheduled for publication, the Japan Prize Foundation announced it would honor Cooper and his achievements.

Cooper was one of the founders of modern immunology. We connect his early work with his lab’s more recent focus on lampreys, primitive parasites with surprisingly sophisticated immune systems.

Molecules from animals with exotic immune systems can be big business, as Andrew Joseph from STAT News points out. Pharmaceutical giant Sanofi recently bought a company focused on nanobodies, originally derived from camels, llamas and alpacas, for $4.8 billion.

Lampreys’ variable lymphocyte receptors (VLRs) are their version of antibodies, even though they look quite different in molecular terms. Research on VLRs and their origins may seem impractical. However, Cooper’s team has shown their utility as diagnostic tools, and his colleagues have been weaponizing them, possibly for use in cancer immunotherapy.

CAR-T cells have attracted attention for dramatic elimination of certain types of leukemias from the body and also for harsh side effects and staggering costs; see this opinion piece by Georgia Tech’s Aaron Levine. Now many research teams are scheming about how to apply the approach to other types of cancers. The provocative idea is: replace the standard CAR (chimeric antigen receptor) warhead with a lamprey VLR.

Read more

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Navigating monstrous anticancer obstacles

A new PNAS paper from geneticist Tamara Caspary’s lab identifies a possible drug target in medulloblastoma, the most common pediatric brain tumor. Come aboard to understand the obstacles this research seeks to navigate. Emory library link here.

Standard treatment for children with medulloblastoma consists of surgery in combination with radiation and chemotherapy. Alternatives are needed, because survivors can experience side effects such as neurocognitive impairment. One possibility has emerged in the last decade: inhibitors of the Hedgehog pathway, whose aberrant activation drives growth in medulloblastoma.

Medulloblastoma patients are caught “between Scylla and Charybdis”: facing a deadly disease, the side effects of radiation and/or existing Hedgehog inhibitors. From Wikimedia.

As this 2017 Oncotarget paper from St. Jude’s describes, Hedgehog inhibitors are no fun either. In adults, these agents cause muscle spasms, hair loss, distorted sense of taste, fatigue, and weight loss. In a pediatric clinical trial, the St. Jude group observed growth plate fusions, resulting in short stature. The drug described in the paper was approved in 2012 for basal cell carcinoma, a form of cancer whose growth is also driven by the Hedgehog pathway. Basal cell carcinoma is actually the most common form of human cancer, although it is often caught at an early stage that doesn’t require harsh treatment.

Caspary’s lab studies the Hedgehog pathway in early embryonic development. In the PNAS paper, former graduate student Sarah Bay and postdoc Alyssa Long show that targeting a downstream part of the Hedgehog pathway may be a way to avoid problems presented by both radiation/chemo and existing Hedgehog inhibitors. Read more

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A sickly sweet anticancer drug

Cancer cells are well known for liking the simple sugar glucose. Their elevated appetite for glucose is part of the Warburg effect, a metabolic distortion that has them sprinting all the time (glycolysis) despite the presence of oxygen.

A collaboration between researchers at Winship Cancer Institute, Georgia State and University of Mississippi has identified a potential drug that uses cancer cells’ metabolic preferences against them: it encourages the cells to consume so much glucose it makes them sick.

Their findings were published in Oncotarget. Read more

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Exosomes as potential biomarkers of radiation exposure

Kishore Kumar Jella, PhD

Winship Cancer Institute postdoc Kishore Kumar Jella has been invited to speak at the NATO advanced research workshop BRITE (Biomarkers of Radiation In the Environment): Robust tools for Risk Assessment in Yerevan, Armenia, on 28-30 November, 2017. The workshop brings together leading international experts to evaluate currently and developing radiation biomarkers for environmental applications.

Jella works in the Departments of Biochemistry and Radiation Oncology under the direction of Professors William S. Dynan and Mohammad K. Khan. He will speak on “Exosomes as Radiation Biomarkers”. He will describe how radiation influences exosome production and how these exosomes influence the immune system. The work has applications both to radiation carcinogenesis and combination radio-immunotherapy.

Jella is supported in part by a grant from the National Aeronautics and Space Administration to Dynan.

Exosomes are nano-sized membrane-clothed capsules containing proteins and RNA that are thought to facilitate cell-cell communcation. They were previously implicated in the ability of cancer cells to influence healthy neighbor cells, and have also been proposed as anti-cancer therapeutic vehicles. Jella’s previous research on exosomes and radiation-induced bystander signaling was published in Radiation Research in 2014.

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Virus hunting season open

New viruses have been popping up in industrial water-cooling towers, in Antarctica and salty deserts. Erwin van Meir, from Winship Cancer Institute of Emory University, and his collaborators managed to find two inside someone’s metastatic tumor.

Working with Terry Fei Fan Ng and Eric Delwart from UCSF, Van Meir identified two new species of anellovirus, a family of viruses first discovered in the 1990s. The new viruses come from a patient with a melanoma that had metastasized to the brain and was operated on at Emory University Hospital.

The results were recently published in Oncotarget.

“We have no evidence that these two viruses were involved in the tumor’s formation, but the data are proof of principle that the metagenomics method used can discover more unknown viruses in human brain tumors,” Van Meir says.

Erwin Van Meir, PhD

Metagenomics is the study of genetic material obtained directly from the environment. The approach is often used to study bacteria, but it is equally valid for viruses. In this paper, investigators used enzymes to chew up human and bacterial DNA, enriching for viral DNA protected by the viral capsid.

Estimates from the USAID’s PREDICT program point to thousands or even millions of viruses, present in mammals and birds, which remain unknown to humans. According to Annual Review of Virology from this summer, Viruses with Circular Single-Stranded DNA Genomes are Everywhere! – and that includes Anelloviridae, for which there is “still no convincing direct causal relation to any specific disease.”

Anelloviruses are relatively primitive in that they do not encode a viral polymerase (the enzyme that copies DNA) and thus need to rely upon the host cell and replicate inside the nucleus. The new ones were named Torque teno mini virus Emory1 (TTMV Emory1) and Torque teno mini virus Emory2 (TTMV Emory2). The research team gave a nod to Emory by using its colors in the virus genome cartoons accompanying the publication. Read more

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Cancer drug discovery: targeting DNA repair

Standard anticancer treatments, such as chemotherapy, target rapidly dividing cells by damaging their DNA. A newer strategy is to undercut cancer cells’ ability to repair DNA damage.

Radiation oncologist David Yu, MD, PhD

Winship Cancer Institute investigators led by David Yu, MD, PhD have identified a distinct function in DNA double strand break repair for an enzyme called SAMHD1. Depleting or inhibiting SAMHD1 could augment anticancer treatments that induce DNA double-strand breaks, such as ionizing radiation or PARP inhibitor drugs, they suggest. Ionizing radiation is a mainstay of cancer treatment and PARP inhibitors are being developed for several cancer types.

The findings were published this week in Cell Reports (open access).

SAMHD1 was known for its ability to chop up the building blocks of DNA, and had come to the attention of virologists because it limits the ability of retroviruses such as HIV to infect some cell types. The first author of the paper, postdoc Waaqo Daddacha, PhD, previously studied SAMHD1 with virologist Baek Kim, PhD, professor of pediatrics.

Cancer researchers had already sought to harness a retroviral protein called Vpx, which viruses evolved to disable SAMHD1. Acute myeloid leukemia cells use SAMHD1 to get rid of the drug cytarabine, so Vpx can sensitize AML to that drug. The Cell Reports paper shows that virus-like particles carrying Vpx could be deployed against other types of cancer, in combination with agents that induce DNA double-strand breaks. Read more

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Winship summer scholars glimpse the future

Guest post from Megan McCall at Winship Cancer Institute. It is not very often that a high school student has the opportunity to work in a lab or clinic shadowing a world-renowned doctor, but for the past six weeks, ten Georgia high schoolers have done just that at Winship Cancer Institute.

Summer scholars in Medical Simulation Lab. Photo by Megan McCall.

The Summer Scholars Research Program, now in its 16th year, exposes students to a multitude of experiences, such as research from Winship’s top experts, lectures by doctors from a variety of specialties, and field trips to Grady Memorial Hospital and the Centers for Disease Control and Prevention. The students have also seen different parts of Emory’s campus through visits to the School of Medicine’s Medical Simulation Lab and the Health Sciences Research Library.

The SSRP pairs each student with an oncologist with whom they complete their own research project and get an in-depth look at a specific cancer specialty. The program will culminate on Friday (8:30 am to 12:30 pm, C5012) with the students presenting their projects to an audience of their peers, mentors, and the Winship community.

“Our goal with this program is to engage scholars at a young age and promote their interest in cancer research. I view this program as a critical part of my work and as a critical piece of Winship’s mission,” says program director Jonathon Cohen, MD. “The SSRP is a unique opportunity for Winship researchers to interact with some of the brightest young people out there, many of whom we hope to consider as colleagues in the future.”

The students attend weekly lectures with a wide array of speakers including oncologists, cancer survivors, and statisticians. Guest lecturer and 10-year cancer survivor Carolyn Higgins says, “It is wonderful to see such a fresh example of today’s future doctors.”

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Urine tests for prostate cancer could reduce biopsies

In the prostate cancer field, there has been a push to move beyond PSA testing. With urine tests, it may be possible to avoid biopsies for men with suspected prostate cancer.

Martin Sanda, MD is chair of urology and leads Winship’s prostate cancer program

With PSA testing to guide decisions, only one in five men is found via biopsy to have a cancer that is sufficiently aggressive (Gleason score of 7 or higher) to warrant treatment right away.

A recently published paper in JAMA Oncology from urologist Martin Sanda and colleagues in the NCI’s Early Detection Research Network shows the potential of urine testing. Sanda’s team reports that two prostate cancer RNA biomarkers detectable in urine (PCA3 and T2:ERG) could be combined to enhance their discriminatory power and reduce unnecessary biopsies by almost half.

The National Cancer Institute’s Cancer Currents blog has an extensive discussion of the JAMA Oncology paper. Read more

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